Integrins are a large family of cell-surface receptors responsible for mediating cell-cell and cells-to-extracellular-matrix (ECM) adhesion. There are at least 24 different integrins, each a heterodimer composed of an α and β subunit, whose expression is determined by several factors including tissue, stage of development, and various tissue pathologies such as inflammation and cancer. Although they do not possess any intrinsic enzymatic activity themselves, subsequent to ligand binding, integrins translate extracellular cues into intracellular signals by bringing into juxtaposition a complex of cytoplasmic structural and signalling molecules that then interact and determine the cell response. As integrins are involved in most elements of cell behaviour including motility, proliferation, invasion and survival their roles in disease have been widely reported. In fact, some integrins are thought to play an active role in promoting certain diseases including cancer. For example αvβ3 has been implicated in promoting the invasive phenotype of melanoma and glioblastoma, owing to its multiple abilities including upregulating pro-invasive metalloproteinases as well as providing pro-migratory and survival signals. As integrin αvβ3 also is upregulated on endothelial cells of angiogenic blood vessels and may provide similar signals for the development of neo-vessels in cancer, such data have led many pharmaceutical and academic centres to develop antagonists of αvβ3 for therapeutic purposes many of which have been peptides or peptidomimetics. Thus, understanding the structural basis of integrin-ligand interaction would aid design of improved integrin antagonists.
αvβ6 is expressed only on epithelial cells. This integrin is involved in both normal and pathological tissue processes. Thus αvβ6 is upregulated by epithelial cells during wound healing and inflammation. It is likely that the ability of αvβ6 to locally activate TGFβ by binding to its protective pro-peptide, the latency associated peptide (LAP), explains the function of αvβ6 in these transient pathologies. Thus TGFβ can suppress inflammatory responses and epithelial proliferation suggesting that αvβ6 serves as a negative control to dampen-down these processes. However, chronic inflammation can lead to an excess of αvβ6-dependent activation of TGFβ resulting in fibrosis in the lung of experimental animals. It is likely that some pathologies that result in fibrosis in humans may also involve αvβ6-dependent TGFβ activation. Constitutive αvβ6 over-expression in the skin of mice resulted in chronic wounds appearing on a significant number of transgenic animals. Thus, chronic wounds associated with human diseases (e.g. certain forms of Epidermolysis Bullosa) may also promoted or exacerbated by upregulation of αvβ6 on the wound keratinocytes.
Recently, it has become clear that the integrin αvβ6 is a major new target in cancer. Although αvβ6 is epithelial-specific, it is weak or undetectable in most resting epithelial tissues but is strongly upregulated in many types of cancer, often at the invasive front. It has been shown that αvβ6 can promote carcinoma invasion by upregulating MMPs and promoting increased motility so that αvβ6 promotes survival of carcinoma cells by upregulating Akt. These data suggest strongly that αvβ6 is actively promoting the invasive phenotype. This suggestion is supported by the recent report showing that high expression of αvβ6 correlates with a significant reduction in median survival by colon cancer patients.
αvβ6 has been identified as a receptor for foot-and-mouth disease virus (FMDV) in vitro by binding through an RGD motif in the viral capsid protein, VP1.